Hypoxia-inducible factor 1 alpha activates and is inhibited by unoccupied estrogen receptor beta.

Previously, we showed that hypoxia induces ligand-independent estrogen receptor (ER)alpha activation. In this study, we found that hypoxia activated the ER beta-mediated transcriptional response in HEK293 cells in the absence of estrogen. ER beta transactivation was induced by the expression of the hypoxia-inducible factor 1 alpha (HIF-1 alpha) under normoxia. ER beta interacted with HIF-1 alpha, and SRC1 and CBP potentiated the effect of HIF-1 alpha on ER beta-mediated transcription. We then examined the effect of ER beta on HIF1-alpha transactivation. Surprisingly, ER beta attenuated the transcriptional activity of HIF-1 alpha, as measured by HRE-driven reporter gene expression and hypoxic induction of VEGF mRNA in HEK293 cells. Taken together, these data show that HIF-1 alpha activates ER beta-mediated transcription in the absence of a ligand, and ER beta inhibits HIF-1 alpha-mediated transcription.